[Senescence-associated secretory phenotype and inflammaging: the role in cardiovascular diseases.]

Senescent cells take part into development the age-related diseases by formation the SASP: senescence-associated secretory phenotype. SASP is characterized by synthesis of signal molecules include proinflammatory cytokines. SASP promotes the inflammaging - chronic, low-grade, subclinical inflammatory process, that is the one of cardio-vascular diseases risk factor in older age-groups. In the review we describe the key SASP molecules of cardiomyocytes, endotheliocytes and vascular smooth muscle cells and its role in the pathogenesis of age-associated cardiovascular diseases.

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells.

Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117+ cells into mature CD28+T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28+, CD4+, CD8+T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28+T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.

Sirtuins as Possible Predictors of Aging and Alzheimer's Disease Development: Verification in the Hippocampus and Saliva.

Verification of signaling molecules in the saliva is a non-invasive method of diagnosis and evaluation of treatment effectiveness in different pathologies. Sirtuins (SIRT), proteins from NAD-dependent histone deacetylases, are supposed to be involved in the pathogenesis of Alzheimerэs disease. Age-related decrease in sirtuins expression induces many pathophysiological processes that could lead to neurodegeneration. We studied the expression of SIRT1, SIRT3, SIRT5, and SIRT6 in the hippocampus and saliva of humans without neurological pathologies and in patients with Alzheimer's disease of elderly and senile age. In elderly and senile patients, the expression of SIRT1, SIRT3, and SIRT6 in the hippocampus and saliva was 1.5-4.9-fold reduced in comparison with healthy individuals of the corresponding age. In healthy senile persons, the expression of SIRT6 in the hippocampus and saliva was 2.5-4.5-fold lower than in healthy elderly individuals. Measurement of SIRT1, SIRT3, and SIRT6 concentration in the saliva can be used as an additional method for intravital non-invasive diagnosis of Alzheimer's disease in patients of advanced age. SIRT6 concentration in the saliva can be recommended as a marker for assessment of the rate of aging.

[Pineamin increased pineal melatonin synthesis in elderly people].

It was investigated the influence of polypeptide complex Pineamin on the 6-sulfatoxymelatonin (aMT6S) excretion in urine by ELISA test of 55 elderly patients with diminished melatoninsynthesis pineal gland function. Pineamin in course dose 100 mg has increased night level of aMT6S urine excretion in 1,9 times in comparison with relevant value untreated. Similar effect was obtained early for medical drug Epithalamin. Epithalamin also restored melatonin level in human and animals during aging. Thus, Pineamin and Epithalamin have similar stimulate effect on melatonin synthesis in elderly people pineal gland.

[Melatonin as a molecular marker of age-related pathologies].

The review has described melatonin as a prognostic marker of invasive and non-invasive diagnostic of organism aging time and age-related pathology. Decreasing of melatonin level in buccal cells has correlated with patient age. Melatonin level in patients with Alzheimer disease has decreased. Melatonin level in blood plasma has correlated with severity of menopausal syndrome. Melatonin secretion in enterocytes increased during gastric ulcer. In oncology patients was described changes of 6-COMT - metabolite of melatonin in urine in dependent of histology type and stage of disease. Thus, melatonin is the molecular marker, which characterized integral processes in neuro-immuno-endocrine system and can be verified by non-invasive methods in peripheral tissues and biological fluids of organism.

[Molecular markers of Alzheimer disease early diagnostic: investigation perspectives of peripheral tissues.]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of elderly and old age people. For intravital diagnosis of the expression of signaling molecules - AD markers, cerebrospinal fluid (CSF) and peripheral tissues are used: lymphocytes and blood platelets, buccal and olfactory epithelium, skin fibroblasts. There are several changes in the production of hyper phosphorylated form of τ-protein, BACE1 and peptide Аß42 in CSF in case of AD, but CSF taking may have a number of side effects. Less traumatic taking of sampling tissues for the diagnosis of AD is in use of epithelium biopsy and blood portion. An increase in the expression of the hyper phosphorylated form of τ-protein is shown in blood lymphocytes of AD patients. An increase in the content of high molecular weight forms of phosphorylated t-protein and amyloid precursor protein-APP was also revealed in blood platelets of AD patients. Changes in the amount of 2 miRNA families - miR-132 family and miR-134 family were revealed in blood cells 1-5 years before the manifestation of clinical signs of AD. An increase in the concentration of bound calcium, synthesis of peptides Aß40 and Aß42, τ protein was observed in AD skin fibroblasts. In the olfactory and buccal epithelium an increase in the expression of hyper phosphorylated form of τ-protein and Aß peptide was detected in patients with AD. Verification of AD markers in peripheral tissues for biopsy have the important significant for life diagnostics, prevention and and target AD treatment.

[MELATONIN: THE POSSIBILITY TO ANALYSE THE MARKER OF AGE-RELATED PATHOLOGY IN THE BUCCAL EPITHELIUM AND URINE].

Extrapineal and pineal melatonin is the marker of the aging rate of organism making it possible to characterize functional condition of the neuro-immuno-endocrine system. In this article we have used the new method for non-invasive diagnostics of melatonin expression in buccal epithelium and determination of the main melatonin metabolite 6-hydroxymelatonin sulfate (6-HMS) in urine of elderly people. Normal, impaired and enhanced melatonin expression was documented in 20.5%, 43.2% and 36.30% of the patients respectively. Such comprehensive melatonin and 6-COMT studies can be recommended for elderly patients with oncological, neurodegenerative, cardiovascular diseases, and ageing macular dystrophy. Moreover, melatonin expression analysis in buccal cells can be used for integral investigation of biorhythms in elderly people.

Effects of pancragen on the differentiation of pancreatic cells during their ageing.

Expression of differentiation markers was found to be reduced during ageing of pancreatic cells. Tetrapeptide pancragen stimulates the expression of differentiation factors of acinar (Pdx1, Ptfla) and islet of Langerhans (Pdx1, Pax6, Pax4, Foxa2, NKx2.2) cells in "young" and " aged" cultures. Differentiation of acinar and islet pancreatic cells induced by pancragen can be a mechanism underlying its anti-diabetic and anti-inflammatory effects. Thus, transcription factors that regulate differentiation of pancreatic cells are a pharmacological target for pancragen, which allows considering it as an effective tool in the treatment of diabetes mellitus and pancreatitis.

[The expression of differential and matrix remodelling factors in human buccal epithelium in aging].

The expression of signaling molecules MMP2, MMP9, ERBB3, CXCL12, Nkx2.5, CD90 (the markers of remodeling intracellular matrix and cell differentiation) in human buccal epithelium in ageing has been studied. The expression of molecular markers MMP2, MMP9, CD90 end ERBB3 has shown a decrease during ageing, especially in old people compared with persons of mature age. These data have demonstrated, that buccal epithelium may be considered as a perspective object to study the aging processes in organism as a whole (on the decrease of cell for differentiation and remodeling intracellular matrix).

[Buccal epithelium as an object for testing of biological age and the speed of aging].

Testing of biological age and the speed of aging is one of the main goal of gerontology and predictive medicine. This review summarizes the ability of using buccal epithelium as target of non-invasive investigation of aging diagnostics. Buccal epithelium used for thelomere test and morphological characteristics of its nucleus demonstrate the speed of aging. The electrophysiological investigation of buccal cells nucleus are the markers of biological age of a human. In future it can be possible to use buccal epithelium for immunogistochemical investigation with goal to diagnose cellular senescence.

Molecular cellular mechanisms of peptide regulation of melatonin synthesis in pinealocyte culture.

The effects of epithalone and vilone peptides on the synthesis of melatonin and factors involved in this process, arylalkylamine-N-acetyltransferase (AANAT) enzyme and pCREB transcription protein, were studied in rat pinealocyte culture. Epithalone stimulated AANAT and pCREB synthesis and increased melatonin level in culture medium. Simultaneous addition of norepinephrine and peptides into the culture potentiated the expression of AANAT and pCREB.

[Melatonin as a marker of intensity of structural and functional changes in the heart and vessels of the patients presenting with metabolic syndrome].

It is known that pathological characteristics of cardiac rhythm variability, endothelial dysfunction, and left ventricular hypertrophy may be used as independent predictors of cardiovascular complications; their combination with metabolic disorders increases severalfold the risk of cardiovascular catastrophes. The patients presenting with metabolic syndrome are characterized by the interrelation between melatonin hypersecretion, parameters of hyperactivity of the sympathetic component of the nervous system, and prognostically unfavourable variants of cardiac and vascular remodeling (including endothelial dysfunction, concentric remodeling and concentric myocardial ventricular hypertrophy). These correlations have age-specific peculiarities.

[Tetrapeptide stimulates functional activity of the pancreatic cells in aging].

In this study the molecular mechanisms of pancreoprotective action of researched tetrapeptide H-Lys-Glu-Asp-Trp-NH2 in aging pancreatic cells of a human were investigated. It is established that the studied tetrapeptide increases the expression of matrix metalloproteinase MMP2, MMP9, serotonin, glycoprotein CD79alpha, antiapoptotic protein Mcl1, proliferation markers PCNA and Ki67 and decreases the expression of proapoptotic protein p53 in aged pancreatic cell cultures. Thus, the capability to activate the expression of signaling molecules--markers of functional activity of pancreatic cells lies behind the clinical effect of studied tetrapeptide observing in elderly patients with type 2 diabetes mellitus.

[Neuroimmunoendocrine mechanisms of aging].

The review discusses in detail the mechanisms of aging from the position of common signaling molecules produced in three regulatory systems: the nervous, endocrine and immune ones. It is shown that the neuroimmunoendocrine hormonal regulation of homeostasis plays the important role in the complex chain of processes that lead to aging of cells, tissues, organs and body as a whole. Particular attention is paid to morpho-functional involution of nervous, endocrine and immune systems, which is accompanied by a breach of elaborate signaling molecules. Detailed analysis and further development of integrated molecular commonality of views on the regulatory systems of both the central and especially local levels, opens vast new opportunities for deepening knowledge of the mechanisms of aging, as well as for the prevention, diagnosis and treatment of diseases associated with aging, in which pathogenesis the discoordination of neuro-immuno-endocrine signaling mechanisms plays an important role.

[The role of melatonin in the development of metabolic syndrome].

The level of 6-oxymelatonin sulfate, the main metabolite of melatonin (MT), in morning urine samples from patients with metabolic syndrome (MS) suggests enhanced MT production at night. This inference equally holds for aged and elderly patients despite their significantly impaired MT secretion due to age-related involution of the pineal gland. Correlation between MT hypersecretion and manifestations of MT activity also depends on the patients" age. MT test can be used as biological marker of MT and a prognostic factor of MS progress.

[Expression of beta-amyloid and tau-protein in mastocytes in Alzheimer disease]. / Ekspressiia beta-amiloida i tau-proteina v tuchnykh kletkakh pri bolezni Al'tsgeimera.

With immunochemical assay, the expression of B-amyloid and tau-protein in the mast cells of the stomach and skin was first detected in patients with Alzheimer's disease (AD), which supports the hypothesis that AD is a systemic disease involving different organs and tissues. Verification of expression of two key peptides that participate in the pathogenesis of AD in the samples of extra-brain tissues allows B-amyloid and tau-protein to be regarded as promising markers and mast cells to be considered to the most suitable object for lifetime diagnosis of neurodegenerative diseases.

[Melatonin for diagnosis of cancer and assessment of prognosis in elderly patients]. / Melatonin v diagnostike i ostenke prognoza zlokachestvennykh opukholei u pozhilykh liudei.

A review is given on the analysis of melatonin (MT) and of its main peripheral metabolite 6-sulfatoxymelatonin (aMT6s) in old patients with different types of primary unoperated carcinomas. A very low production of melatonin (as estimated by the nocturnal urinary excretion of aMT6s) was found in male patients with lung or stomach cancer compared to aged-matched controls as well as in female patients with thyroid cancer. The levels of these women, however, did not differ from female patients with benign thyroid diseases indicating a general suppressive effect of thyroid diseases on the pineal gland. A similar but opposite phenomenon was observed in male patients with primary unoperatide colorectal cancer which showed an elevated production of mellatonin when compared to healthy men but not when compared to patients with colitis ulcerosa. The mechanisms involved in these phenomena are poorly understood and seem to include central as well as peripheral components. This view is supported by the finding that in spite of varying urinary aMT6s excretion measured in patients with different types of tumor, aMT6s shows comparable positive correlations with the degree of tumor cell proliferation (as estimated by the number of PCNA-immunopositive cells). Therefore the amount of aMT6s excreted (as well as the corresponding concentration of circulating MT) has to be understood as the net result of a number of different effects by the tumor on organism.

[Melatonin and serotonin in inflammatory colon diseases and colorectal neoplasms]. / Melatonin i serotonin pri vospalitel'nykh zabolevaniiakh tolstoi kishki i kolorektal'nom rake.

Patients with inflammatory intestinal diseases and colorectal adenocarcinoma in sigmoid mucosa were examined using light and electron microscopy, immunohistochemical tests, radioimmunoassay and morphometry. Functional morphology of the general population of the endocrine cells and apudocytes producing melatonin and serotonin as well as urine excretion of 6-sulfatoxymelatonin changed in quality and quantity. The parameters showed specificity depending on clinicomorphological variant of colorectal pathology. The findings provide additional criteria in diagnosis and prediction of the course of different types of inflammatory and tumor affections of the colon.